The use of mushroom glucans and proteoglycans in cancer treatment

Abstract

Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor - PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide - have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens.

Full text

Page 4 Alternative Medicine Review
◆ Volume 5 Number 1 ◆ 2000
Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
The Use of Mushroom Glucans and
Proteoglycans in Cancer Treatment
by Parris M. Kidd, PhD
Parris Kidd, PhD (Cell biology, University of California at Berkeley); Contributing Editor, Alternative Medicine Review; Health
educator and biomedical consultant to the supplement industry.
Correspondence address: 535 Pierce St. Suite 209 Albany, CA 94706.
Abstract
Immunoceuticals can be considered as substances having immunotherapeutic efficacy
when taken orally. More than 50 mushroom species have yielded potential
immunoceuticals that exhibit anticancer activity
in vitro
or in animal models and of
these, six have been investigated in human cancers. All are non-toxic and very well
tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated
Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-
Fraction has limited proof of clinical efficacy to date, but controlled research is underway.
Two proteoglycans from
Coriolus versicolor
– PSK (Polysaccharide-K) and PSP
(Polysaccharide-Peptide) – have demonstrated the most promise. In Japanese trials
since 1970, PSK significantly extended survival at five years or beyond in cancers of
the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types),
and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and
Phase III trials in China. In double-blind trials, PSP significantly extended five-year
survival in esophageal cancer. PSP significantly improved quality of life, provided
substantial pain relief, and enhanced immune status in 70-97 percent of patients with
cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted
immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor
infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven
benefits to survival and quality of life, and compatibility with chemotherapy and radiation
therapy makes them well suited for cancer management regimens.
(
Altern Med Rev
2000;5(1):4-27)
Introduction
As the new millennium dawns, humanity continues to strive for longer lifespan and
better quality of life. But the disease of cancer continues to be the scourge of humanity; being a
leading cause of early death, and resistant to therapies aimed at its eradication. Now another
dimension of anticancer therapy is available – immunotherapy, a means by which the body’s
immune defenses, beaten down by the cancer and by toxic therapies used against the cancer,
can be revitalized to carry out their natural functions of eliminating abnormal tissues from the
body. The tools for immunotherapy are naturally-occurring substances, herein christened
immunoceuticals, which can be included in the general category of nutraceuticals, or dietary
supplements.

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 5
Mushrooms have
been recognized for their
medicinal properties for five
millennia.
1
It was not until
the last one-third of the past
century that technology was
capable of biochemically
dissecting traditional medici-
nal mushrooms and isolating
their most active anticancer
constituents. Once concen-
trates of such substances be-
came reliably available, they
were screened in animal
models of cancer prior to ap-
propriate anticancer applica-
tion in humans. Some of
these mushroom-derived
substances were found to be
highly potent immune sys-
tem enhancers, potentiating
human immunity against
cancer more effectively than
other anticancer agents. This
review focuses on mushroom
immunoceuticals; prepara-
tions from mushrooms
which have been systemati-
cally investigated for their
oral anticancer action.
Mushroom Immunoceuticals – An
Overview
Immunoceuticals isolated from more
than 30 mushroom species have shown
anticancer action in animals.
2
Only a handful
have been taken to the next step: objective
clinical assessment for anticancer potential in
humans. Of these relative few, all are
chemically ß-D-glucan in nature (i.e., linear
polymers of d-glucose with other
monosaccharides) or ß-D-glucans linked to
proteins (so-called polysaccharide-peptides,
more formally termed “proteoglycans”– see
Figure 1). As a rule, the protein-linked glucans
have greater immuno-
potentiation activity than the
corresponding free glucans.
3
The basic ß-D-
glucan is a repeating struc-
ture, with its D-glucose mol-
ecules joined together in lin-
ear chains by beta-bonds (ß).
These can extend from the
carbon 1 of one saccharide
ring to the carbon 3 of the
next (ß1-3), from carbon 1
to carbon 4 (ß1-4), or from
carbon 1 to carbon 6 (ß1-6).
Most often there is a main
chain which is either ß1-3,
ß1-4, or mixed ß1-3, ß1-4
with ß1-6 side chains. The
basic repeating structure of
a ß1-3 glucan with ß1-6 side
chains is shown in Figures
2a and 2b. Hetero-ß-D-
glucans, i.e., linear polymers
of glucose with other D-
monosaccharides, can have
anticancer activity, but al-
pha-D-glucans from mush-
rooms usually lack antican-
cer activity.
6
Six mushroom
preparations have shown
clinically significant efficacy against human
cancers: lentinan, schizophyllan, Active Hex-
ose Correlated Compound (AHCC), Maitake
D-Fraction, Polysaccharide-K, and Polysac-
charide-P. Since lentinan and schizophyllan
have limited oral bioavailability, and therefore
fail to meet the definition of immunoceutical,
they will only be given a cursory review.
AHCC and Maitake D-Fraction are still in the
early stages of investigation. The remaining
two have been subjected to in-depth applica-
tion against cancers in humans.
Glucan Chains
Core Proteins
or Polypeptides
Figure 1. The molecular plan of
a mushroom proteoglycan. The
central, linear polypeptide chain
has multiple, branched chains of
poly-beta-D-glucans attached.
Modified from Molecular Biology of the Cell.
7

Page 6 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
Lentinan from Shiitake
Lentinan, produced from the Shiitake
mushroom Lentinus edodes, is a ß1-3, ß1-6 D-
glucan. Glucan preparations are always het-
erogeneous in molecular weight, but lentinan
is particularly large, on the order of 400,000-
1,000,000 daltons. Its oral bioavailability is
reportedly limited; thus, it has been routinely
administered intravenously. Open-label clini-
cal studies indicate lentinan can prolong life
in patients with gastric or colorectal cancer,
as reviewed recently by Borchers et al.
1
Lentinan has been satisfactorily proven to po-
tentiate human immunity.
1,2,8
Schizophyllan (SPG, Sonifilan,
Sizofiran, Sizofilan)
Schizophyllan, from Schizophyllum
commune, is another ß1-3, ß1-6 D-glucan too
large for effective oral administration. Its mo-
lecular weight ranges around 450,000 daltons
and it is usually administered by intramuscu-
lar injection. Schizophyllan was found rather
ineffective against gastric cancer, but extended
survival time in patients with head and neck
cancer.
1,9
In cervical cancer, schizophyllan pro-
longed survival and time to recurrence for
stage II cases but not stage III,
10-12
and showed
added effectiveness when injected directly into
the tumor mass.
13
Active Hexose Correlated
Compound (AHCC)
Active Hexose Corre-
lated Compound (AHCC) is a
proprietary extract prepared from
co-cultured mycelia of several
species of Basidiomycete mush-
rooms, including shiitake
(Lentinus edodes). Mushroom
sources and details of the meth-
ods of preparation have not been
fully disclosed.
14
The extract is
made using hot water following
an enzyme pretreatment; it contains polysac-
charides, amino acids, and minerals, and is
orally bioavailable. According to its manufac-
turers, the glucans in AHCC have low molecu-
lar weight (around 5,000 daltons) and are of
the alpha-1,3 type.
14
Both these attributes are
peculiar for immunoactive mushroom glucans
– typically such low-molecular weight mate-
rial is inactive, and as a rule the alpha-glucans
have minimal immuno-potentiating activity;
HO
CH
2
OH
O
OH
6
1
23
β
CH
2
OH
O
OH
1
HO
CH
2
O
OH
6
1
23
β
O
HO
CH
2
OH
O
OH
6
1
23
β
O
O
β
O
β
HO
OH
n
Figure 2a. Primary molecular diagram of
mushroom beta-D-glucans.
From Yanaki et al
4
6
6
6
6
6
6
3
3
3
2
2
2
2
2
1
1
1
β
β
2
Figure 2b. Higher-level molecular
diagram of mushroom
beta-D-glucans. From Bluhm
5

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 7
yet animal research and preliminary human
studies indicate AHCC has anticancer efficacy.
Beginning in 1992, Kamiyama
conducted a trial in Japan to evaluate the
preventive effect of AHCC against recurrence
of hepatocellular carcinoma following surgical
resection.
15
After surgery, 126 patients were
separated into two groups: 44 patients were
administered AHCC, 3 grams per day orally,
while the other 82 served as controls.
Unfortunately, the outcome of this trial is
published to date only in abstract form. The
investigators reported that after one year the
AHCC group showed a significantly higher
survival rate than the control group, as well as
significant lowering of certain tumor markers
in the serum.
In another published abstract based on
this same study, Kamiyama et al stated liver
tumor recurrence was not lower in the AHCC
group, although the survival rate was higher.
16
They claimed AHCC-treated patients who ex-
perienced improved survival were positive for
hepatitis C; and patients who were either hepa-
titis B-positive or negative for hepatitis viruses
did not experience better survival rates. They
reported the AHCC-treated patients also had
significantly decreased levels of liver damage
markers SGOT and SGPT. Among these pa-
tients, significant improvements were noted in
lymphocyte and red cell counts, and in appe-
tite and anemia.
14
In four cases where cirrho-
sis was also present, ascites developed and was
successfully treated with 3-6 grams/day of
AHCC.
The AHCC Research Association was
formed in Japan in 1996 to foster the develop-
ment of AHCC as an anticancer therapy. In
their circulating abstracts
14
they report on other
preliminary studies with AHCC against can-
cer. They state that of 300 cancer patients ad-
ministered AHCC, 58 were effectively treated,
with 46 showing complete or partial regres-
sion and 12 experiencing no change of tumor
size. Among these 58 cases were cancers of
the lung, breast, stomach, esophagus, colon,
liver, and several other sites. It is not possible
from the limited data to calculate relative effi-
cacies, improvements in survival or recurrence,
or quality of life benefit for any of these can-
cers. Research on AHCC is at a comparatively
early stage, but its declared efficacy against
liver cancer warrants further investigation.
Maitake D-Fraction
Maitake D-Fraction is a mixed ß-D-
glucan fraction prepared from the maitake
mushroom (Grifola frondosa) and is orally
bioavailable (see Jones
17
for an overall review).
Maitake has been used as food in Japan for
hundreds of years, in amounts up to several
hundred grams per day, and its safety is estab-
lished. A hot-water extract from the fruiting
body of the mushroom was found to be highly
potent against human cancer cells in culture.
Subsequently, the D-fraction was prepared
from the crude hot-water fraction by
deproteination.
17
Maitake D-Fraction contains mainly ß-
D-glucan material with 1-6 main chains and
1-4 branchings, and the more common 1-3
main chains and 1-6 branchings.
18
This frac-
tion also is highly active in vitro and in animal
models of cancer, although activity in these
experimental systems does not necessarily pre-
dict anticancer efficacy in humans.
Maitake D-Fraction has been used in
a few exploratory studies in cancer patients.
17
In 1994, a group from China published in ab-
stract form their findings from a pilot study
on 63 cancer patients. They reported the total
effective rate against solid tumors at higher
than 95 percent, and the effective rate against
leukemia higher than 90 percent.
17
Unfortu-
nately, the concentration of the extract used
was not disclosed.
In 1995, Nanba published an informal
summary of an open-label, non-randomized
study conducted in Japan.
19
In this study, 165
patients with various cancers, many with

Page 8 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
advanced progression and some refusing
chemotherapy, were treated with D-Fraction
plus tablets of dried crude extract of maitake.
Dosages varied from patient to patient, with
D-fraction doses ranging from 35-100 mg per
day and crude mushroom extract ranging from
4-6 grams. Symptomatic improvements or
regression were claimed for approximately 73
percent of the breast cases and 67 percent of
the lung cases. Of the liver cancer cases, 47
percent were said to have responded, which
jumped to 73 percent when chemotherapy was
also utilized. In contrast to the incredible
response rates claimed in the Chinese study,
in the Japanese study less than 50 percent of
the leukemias and cancers of the prostate,
brain, stomach, and bone seemed to respond.
The disease subgroups were small, however,
the largest number of cases studied being 19
(liver cancer, with chemotherapy). According
to Nanba, 83 percent of the patients
experienced lessening of pain, and 90 percent
experienced improvement of chemotherapy-
related symptoms such as vomiting, nausea,
reduced appetite, hair loss, intestinal bleeding,
and lowered white cell count.
These claims of benefit from Maitake
D-fraction are encouraging. In the absence of
adequate peer review and especially without
access to the primary data, however, it is diffi-
cult to assign meaning to them. Nonetheless,
several U.S. physicians have reported good
results with Maitake D-fraction in their prac-
tices, and an Investigative New Drug approval
was obtained in 1998 to begin a Phase II pilot
study with this material on patients with ad-
vanced breast and prostate cancer.
20
Proteoglycans from Coriolus
versicolor
The mushroom-derived “polysaccha-
ride-peptides,” or proteoglycans, are polypep-
tide chains or small proteins to which polysac-
charide ß-D-glucan chains are stably attached.
Up to this point, PSK and PSP are the only
two proteoglycans systematically investigated
in human cancers.
Coriolus versicolor (formerly
Trametes versicolor, Polyporus versicolor) is
a mushroom which grows on tree trunks and
belongs to the more-advanced Basidiomycetes
class of fungi. This mushroom has long been
treasured in the East; in Japan it is known as
kawaratake (“mushroom by the river bank”),
and in China it is called Yun Zhi or “cloud fun-
gus.” In Japan around 1965 a chemical engi-
neer investigated Coriolus versicolor for its
anticancer constituents after observing his
neighbor’s life-threatening cancer was cured
after taking Yun Zhi. This led to the discovery
of PSK (Polysaccharide-K).
21
The closely-re-
lated PSP (Polysaccharide-Peptide) was first
isolated in China some time later, around
1983.
22
PSK Constituents
PSK is prepared from strain CM-101
of Coriolus versicolor by water extraction and
salting out. It is approximately 62-percent
polysaccharide and 38-percent protein, al-
though the content of both can vary. The glucan
portion of PSK consists of a ß1-4 main chain
and ß1-3 side chains, with ß1-6 side chains
that bond to a polypeptide moiety through O-
or N-glycosidic bonds. The polypeptide por-
tion is relatively rich in aspartic, glutamic, and
other acidic amino acids. PSK is a set of mol-
ecules whose molecular weight ranges from
94,000 to 100,000 daltons, and is bioavailable
by the oral route.
23
Studies with C14-labeled
PSK in mice confirmed its full molecular spec-
trum is absorbed within 24 hours following
administration. Conventional toxicological
assessments indicate PSK is non-toxic: its oral
LD50 is low and no abnormalities have been
observed in subacute and chronic toxicity tests.
PSK Clinical Trials
The first clinical trial research with
PSK began around 1970. Decades of clinical

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 9
experience indicate PSK is very gentle on
cancer patients, its only significant side-effect
being occasional darkening of the fingernails.
To date, PSK is most clinically indicated for
cancers of the stomach, esophagus,
nasopharynx, colon, rectum, and lung (see
Tables 1 and 2). It has also shown promise in
a subset of breast cancers.
Stomach Kaibara et al, 1976
24
66 PSK w/chemo doubled 2-yr
Stage IV Surgery w/MMC survival (p<0.05), incl. pts w/
w/inv., metas. +/- PSK w/chemo invasion-metastasis
Stomach Fujimoto et al, 1979
25
230 PSK w/chemo extended
all stages Surgery +/- PSK w/ survival of one subset (p<0.001)
chemo but not poor immune responders
Stomach Hattori et al, 1979
26
110 PSK w/chemo improved 3-yr
Stages I-IV Surgery w/MMC survival (poor stat. analysis)
+chemo +/-PSK PSK no deaths stage III 2 yrs
Stomach, Adv. Kodama et al, 1982
27
450 PSK w/chemo doubled
w/inv., metas. Surgery w/MMC 5-yr survival (p<0.01)
+/- PSK w/chemo
Stomach Kondo and Torisu, 1985
28
144 PSK extended disease-free
Stage III Surgery/no chemo +/-PSK period (no p-value given);
DOUBLE-BLIND enhanced immunity (p<0.05)
Stomach Mitomi, Ogoshi, 1986
29
168 PSK extended 5-yr survival
Stages I-IV Surgery + chemo +/-PSK (p<0.05)
Stomach, Adv. Niimoto et al, 1988
30
579 PSK extended 5-yr survival
w/inv., metas. Surgery w/MMC (p<0.05); pre-op immunity
+/-chemo +/-PSK predicted PSK benefit
Stomach, Adv. Maehara et al, 1990
30
255 PSK w/chemo extended 15-
w/inv., metas. Surgery +/- PSK w/chemo yr survival (p<0.035)
Stomach Tsujitani et al, 1992
34
53 PSK extended 5-yr survival
Stage III Surgery + MMC + chemo (p<0.05)
+/-PSK
Stomach, I-IV Nakazato et al, 1994
32
253 PSK extended 5-yr survival
Surgery + chemo +/-PSK (p<0.05), disease-free
period (p<0.04)
MMC=mitomycin-C; chemo=5-fluorouracil (5-FU) or derivative, long-term, sometimes combined
with other agents; PSK=Polysaccharide-K, at 3-6g/day for 1 year or longer. See individual
references for details.
Cancer type Authors Subjects Outcome
Table 1. PSK: Controlled Trials in Stomach Cancer

Page 10 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
PSK and Stomach Cancer
Stomach cancer continues to inflict
major mortality in Japan and has been the
object of more clinical trials with PSK than
any other cancer. Beginning in 1970, Kaibara
and his colleagues at Kyushu University in
Fukuoka, Japan, began adding PSK
immunotherapy to their existing chemotherapy
protocols.
24
Hoping to achieve a clearcut result
after two years, they chose to study patients
with advanced (Stage IV) cases with invasion
and metastasis, since few such patients survive
an additional two years. They first performed
conventional surgical resection, administering
Mitomycin-C (MMC) beginning on the day
of surgery. The patients were then put on a
long-term chemotherapy regimen of Futraful,
a 5-fluorouracil (5-FU) derivative, with
periodic MMC treatments. PSK was added at
3 grams per day orally. The overall
combination regimen was named
“chemoimmunotherapy.” This group was
retrospectively compared against a patient
group treated in earlier years with surgery and
MMC, but not with the chemoimmunotherapy
regimen.
Kaibara’s group found survival was
better in the chemoimmuno- group by more
than double (34% vs 11%, p<0.05) after two
years.
24
This finding was later supported by a
similar trial conducted by Fujimoto and asso-
ciates at Chiba University.
25
In addition,
Hattori’s group at Hiroshima University did a
trial in which they also monitored immune
competence using skin DTH (delayed-type-
hypersensitivity) reactions and lymphocyte
blastogenesis following induction by mito-
gens.
26
Treatment after surgery with the com-
bination of PSK as immunotherapeutic (6
grams/day) and 5-FU as chemotherapeutic was
again found more effective for long-term sur-
vival of stomach cancer patients compared to
treatment with MMC only after surgery. In this
trial, the combination of PSK with 5-FU very
likely increased three-year survival. Although
the statistical analysis was flawed, survival
data clearly indicated benefit after the first
year, and among Stage III patients taking the
combination all survived greater than two
years. PSK showed a tendency toward protect-
ing against the immunosuppression that typi-
cally accompanies surgery and long-term che-
motherapy. By the early 1980s, once more re-
inforced by the results of Kodama et al,
27
the
use of PSK as the immuno-component of
chemoimmunotherapy consistently doubled
the two-year survival rate for stomach cancer
in Japan.
In a 1985 double-blind trial with PSK
in stomach cancer, patients with Stage III stom-
ach cancer were treated with PSK or a pla-
cebo post-surgery, without the use of chemo-
therapy.
28
PSK significantly extended the dis-
ease-free period over 80 months, although sur-
vival rate was not significantly extended. The
investigators criticized their decision to admin-
ister PSK so tentatively: 3 grams/day for the
first two months, 2 grams/day for up to 14
months, then 1 gram/day thereafter for the re-
mainder of the trial. They speculated their re-
sults would have been better had PSK been
given at 3 grams/day for the duration of the
trial. The only statistically significant adverse
effect from PSK was darkened pigmentation
of the fingernails, occurring in four of 77 pa-
tients. After two months on PSK in this trial,
patient immunocompetence was significantly
improved, as judged by increased DTH (de-
layed-type hypersensitivity) on skin tests and
enhanced chemotactic migration of neutro-
phils. Interestingly, this group also found PSK
would improve DTH in aged men who had
lowered immunity, but did not have cancer. As
the trials progressed it became evident that
individuals with very low immunity were less
likely to benefit from PSK therapy than were
individuals with some degree of remaining
immunity.
During the 1980s and 90s, four trials
established that PSK improved survival in

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 11
stomach cancer patients up to five years, in-
cluding some patients with advanced Stage III
and IV cases with metastasis.
29-32
Another trial
conducted during this period, which enrolled
more than 5,400 participants, had design flaws
that make it useless to inter-
pret.
33
A 1986 trial by
Mitomi and Ogoshi was the
first attempt to separate the
PSK-induced increase in
stomach cancer survival from
the effects of long-term che-
motherapy. Significantly bet-
ter five-year survival was re-
ported with PSK. Two years
later, in the Niimoto prospec-
tive randomized trial on 579
patients,
30
another direct
comparison of long-term che-
motherapy versus long-term
chemotherapy with PSK also
concluded that PSK contrib-
uted significantly to five-year
survival (p<0.01). Further-
more, patients found to ben-
efit most from PSK were
those with invasion and/or
metastasis and those with bet-
ter immune competence prior
to surgery, as measured by
skin DTH tests.
After Maehara’s
group showed PSK combined
with chemotherapy can im-
prove survival as far as 15
years (see Figure 4a),
31
their
group investigated possible
connections of PSK-respon-
siveness with known immu-
nity mechanisms.
34
Tsujitani
et al at Kyushu University
observed earlier that dendritic
cells could infiltrate cancer-
ous stomach lesions in their
patients.
34
Further examina-
tion of biopsy material revealed that patients
who achieved extended survival were those
who exhibited the most marked dendritic cell
infiltration of their tumors prior to surgery.
100
90
80
70
60
50
40
30
20
10
0
012345
Immunochemotherapy (n=12)
Chemotherapy (n=12)
Years after gastrectomy
Percent Survival
100
90
80
70
60
50
40
30
20
10
0
012345
Immunochemotherapy (n=20)
Chemotherapy (n=9)
Years after gastrectomy
Percent Survival
Figure 3. Survival rates of stomach cancer patients
with marked dendritic cell infiltration (top) or slight
infiltration (bottom), given either chemotherapy
alone or chemotherapy with PSK
(immunochemotherapy).
From Tsujitani et al, 1992.
34

Page 12 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
Certain immune cells which resemble
macrophages are located in the skin and virtu-
ally all other tissues, and very likely act as an
early warning system for the body’s immune
defenses. Having dendritic or finger-like pro-
jections, they are called dendritic cells, unless
they are present in the skin, where they are
termed Langerhans cells. These immune cells
often are the first to detect the presence of for-
eign antigens and initiate an appropriate re-
sponse against them. These cells first ingest
the foreign material, then break it down to
smaller pieces. Subsequently they can
“present” the antigens to T-cells, with which
they habitually interact at close range to co-
operatively mount immune responses, includ-
ing cytotoxic activity against cancerous tissue.
Dendritic-killer cell coordinated responses are
the prototypical mechanism for tumor cell kill-
ing.
Further retrospective examination of
tissue samples from 53 patients with Stage III
stomach cancer, of whom 20 had received PSK
as immunotherapy, demonstrated that among
patients manifesting marked tumor infiltration
by dendritic cells at the time of surgery, five-
year survival was greater than 90 percent; yet
PSK did not significantly enhance survival.
Among patients with low dendritic cell infil-
tration, five-year survival was a mere 10 per-
cent. Thus, of nine such patients subjected to
conventional chemotherapy without PSK,
none survived beyond three years. Of 20 who
received the same chemotherapy regimen with
PSK, nine (45 percent) were still alive at three
years. (see Figure 3) The investigators con-
cluded for stomach cancer patients who show
limited dendritic cell infiltration prior to sur-
gery, PSK immunotherapy is likely to signifi-
cantly increase their chance for long-term sur-
vival.
In 1994, The Lancet published the find-
ings from a well-designed trial on PSK therapy
in the treatment of stomach cancer conducted
by the Study Group of Immunochemotherapy
with PSK for Gastric Cancer of Japan.
32
Che-
motherapy with PSK was compared against
chemotherapy without PSK, and PSK was
again found to significantly improve both five-
year survival and disease-free survival (see
Figure 4b). No toxic effects could be observed
for PSK, “even after meticulous review of all
the patient records.…” Although the exact
degree of benefit from PSK was subsequently
challenged,
35
this trial has great clinical sig-
nificance.
PSK and Colorectal Cancer
As its benefits to stomach cancer be-
came established, PSK was assessed for its
potential anticancer activity in patients with
advanced colorectal cancer. In an eight-year,
double-blind trial,
36
111 patients with
colorectal cancer (pathologic stages III and IV,
Dukes Stage C) were randomized into two
groups, then administered PSK or placebo in
decreasing doses over time, as per Kondo and
Torisu’s earlier gastric cancer study. PSK, 3
grams/day, was given until two months after
surgery, followed by 2 grams/day until 24
months, and 1 gram/day thereafter. PSK sig-
nificantly improved both the eight-year sur-
vival rate (to 40% vs. 25%, p<0.05) and the
disease-free interval (to 25% vs 8%, p<0.05).
In 1992, Mitomi et al, in the Coopera-
tive Study Group of Surgical Adjuvant
Immunochemotherapy for Cancer of Colon
and Rectum, published the results of a large
multicenter trial with PSK in colorectal can-
cer.
37
They recruited 448 patients from 35 in-
stitutions in Japan, randomized them into two
groups, then put them through surgery and
chemotherapy plus or minus PSK. After the
third year, PSK had significantly improved sur-
vival and the disease-free period in the colon
group (p<0.05 in both)(see Figure 4c), but not
in the rectal cancer group (p=0.12).

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 13
Table 2. PSK: Controlled Trials in Other Cancers
Cancer Type Authors Subjects Outcome
Colorectal Torisu, Kondo et al, 1990
36
111 PSK extended 8-yr survival
DOUBLE-BLIND Surgery/no chemo +/-PSK (p<0.05), disease-free
period (p<0.05), enhanced
DTH immunity (p<0.05)
Colorectal Mitomi et al, 1992
37
448 PSK extended colon 5-yr
Surgery + chemo +/-PSK survival (p<0.04), disease-
free period (p<0.05); rectal
benefits not sig. (p=0.1)
Esophageal Ogoshi et al, 1995
39
158 PSK extended 5-yr survival
Surgery + radiother. (RT) post- surg+RT+CT (p<0.03);
+/- chemother. (CT) normalized serum factors
+/- PSK
Nasopharyngeal Go and Chung, 1989
41
34 PSK extended 5-yr survival
Radiotherapy (p<0.04), but not disease-
+/- chemother. +/-PSK free period
Lung (NSCLC) Hayakawa et al, 1993
42
185 PSK extended 5-yr survival
Stages I-III Radiother. +/-PSK 2-4x, all stages (p<0.005);
tumors <5cm, age >70 yrs
more benefit (p<0.04, 0.01)
Breast, ER+/- Toi et al, 1992
44
914 PSK extended survival in
Stage II, IIIA MMC +/- Tamoxifen ER-neg, non-metas. Stage II
post-surgery +/- Ftorafur +/- PSK (p<0.002)
Breast, ER+/- Morimoto et al, 1996
45
889 No evident benefit
Stage II MMC+/- Tamoxifen from PSK
post-surgery +/- Ftorafur +/- PSK
Breast Iino et al, 1995,
46
1997
47
227 PSK trend to extended 10-yr
Stages I, II FEMP chemotherapy survival (p=0.07), 10-yr
+ Levamisole or PSK; disease-free period (p=0.1);
compared HLA B40+ HLA B40+ pts. had 100% 10-
vs HLA B40- yr survival (p<0.05)
Leukemia/ANLL Ohno et al, 1984
48
67 Trend to lengthened
in remission remission (p=0.1) in pts.
with remission >270 days
Leukemia/ALL Kawa et al, 1991
49
108 No evident benefit from PSK
in remission

Page 14 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
PSK and Esophageal Cancer
Pre- and post-operative radiotherapy
can improve survival in esophageal cancer. In
1980, Okudaira et al reported on a non-con-
trolled, retrospective analysis of their success
with combined radiation, chemotherapy, and
immunotherapy in 133 cases.
38
They con-
cluded the addition of immunotherapy to the
regimen using either PSK or OK-432 (an
immunopotentiator which has undesirable
side-effects) significantly improved both one-
year and two-year survival.
In the Cooperative Study Group for
Esophageal Cancer in Japan, a prospective,
randomized, multi-center study of 158 esoph-
ageal cancer patients,
39
researchers followed
five-year survival and its relationship to alpha
1-anti-chymotrypsin (ACT) and sialic acid
(SA) levels. These serum-borne substances are
immunosuppressive at high serum levels, but
are sometimes lowered by PSK treatment.
After undergoing surgery, followed by radio-
therapy, patients were randomly assigned to
one of four groups. Two groups received che-
motherapy, one with and one without PSK; the
other two received no chemotherapy, one with
and one without PSK.
After all comparisons were complete,
patients who received PSK (3 grams/day for
three months beginning immediately after sur-
gery) had a significantly better survival rate at
five years (p<0.03). Those with abnormally
high levels of ACT had poor survival unless
they received PSK (26% vs 55%, p<0.008).
The same was true for patients with abnor-
mally high SA (31% vs 58%, p<0.07). This
shows PSK clearly benefits five-year survival
in esophageal cancer and has markedly greater
benefit for those patients with pre-operative
high ACT or SA. Ogoshi and other members
of this group previously reported a similar
pattern in patients with gastric cancer.
PSK and Nasopharyngeal Cancer
Conventional treatment of nasopharyn-
geal carcinoma has involved radiotherapy,
sometimes followed by chemotherapy. In a
small controlled trial carried out in Taiwan,
researchers randomly selected 34 patients who
had received radiotherapy, and administered
to 14 of the patients various forms of chemo-
therapy, using cisplatinum, 5-fluorouracil,
methotrexate, and vincristine. Once this pri-
mary therapy was completed (radiation or ra-
diation plus chemo-), the entire group was ran-
domized to receive PSK (3 grams per day, for
up to two years) or not. As shown in Figure
4d, the PSK group showed significantly ex-
tended survival at five years (28% compared
to 15% for controls, p=0.04).
41
PSK and Lung Cancer
In 1977, Hayakawa and colleagues at
the Gunma University School of Medicine in
Japan began giving PSK to non-small-cell lung
cancer patients post-radiotherapy.
42
After es-
tablishing radiotherapy was only marginally
effective in tumors larger than 2 cm in diam-
eter, they added immune system potentiation
to the regimen. One-hundred-eighty-five pa-
tients with epidermoid carcinoma, adenocar-
cinoma, or large-cell carcinoma, of severity
up to stage IIIB, were enrolled. Each patient
received radiation therapy 6-7 weeks. Sixty-
two were subsequently randomly selected to
receive PSK 3 grams daily, in repeating cycles
of two weeks on and two weeks off. After five
years, almost four times more of the patients
treated with PSK were alive (27% compared
to 7% for those not given PSK, p<0.005) (see
Figure 4e).
The benefit to lung cancer patients
from PSK in this study is clinically significant
in that more-advanced patients with stage III
disease who received PSK had a better
prognosis than stage I and II patients who did
not receive PSK. Furthermore, this trial also
demonstrated PSK given in addition to

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 15
radiotherapy was particularly helpful for older
patients (>70 years, p<0.007) and patients with
smaller primary tumors (£ 5 cm diameter,
p<0.04). When disease stage was factored out,
patients who had higher Karnovsky
performance scores prior to receiving PSK also
had better survival (p<0.02), suggesting the
better-conditioned lung cancer patient stands
to benefit more from PSK.
PSK Selective Effectiveness Against
Breast Cancer
As early as 1984, Sugimachi’s group
at Kyushu University published a retrospec-
tive analysis of breast cancer patients with re-
current disease, all subjected to “surgical hor-
mone therapy” (total ovary and partial adre-
nal gland removal). Some patients then re-
ceived chemotherapy with or without PSK im-
munotherapy.
43
The earliest-treated group
(1961-1969) received only surgical hormone
therapy and served as controls. A later group
(1970-1976) received mitomycin-C immedi-
ately after surgery. An even later group (1970-
1981) received long-term combination chemo-
therapy along with PSK immunotherapy. The
survival rate after recurrence was significantly
extended by the immunochemotherapy, in
comparison to the other two groups. The value
of this type of study is limited because the
patient groups are drawn from different popu-
lations; nonetheless, the findings are marked
and support the use of PSK in breast cancer.
In 1992, a large randomized trial evalu-
ated tamoxifen as an addition to the then-con-
ventional chemotherapy, and factored in PSK
(3 grams daily for two years) as the immuno-
therapy arm. This trial involved 914 patients
who were sub-analyzed by: (1) estrogen re-
ceptor-positive or negative status; (2) extent
of metastatic lymph node involvement; and (3)
classic cancer stage (Stages I-IV). In-depth
analysis revealed PSK significantly extended
survival in ER-negative, Stage IIA T2N1 pa-
tients without lymph node involvement. This
limited finding was later contradicted by
Morimoto’s group,
45
who also did a large trial
and found no statistical evidence of benefit
from PSK.
This seeming paradox may have been
resolved by Iino et al, working at Japan’s
Gunma University.
46,47
Their 1995 trial on
breast cancer patients with vascular invasion
found strong statistical trends for extended 10-
year survival with PSK use (p=0.07), and ex-
tended disease-free period (p=0.1). Their data
suggested clinical effectiveness, yet the sta-
tistics fell short of formal verification. Know-
ing that HLA B40 antigen status had been
linked to likelihood of survival with breast
cancer, the researchers compared their B40-
positive patients treated with PSK against B40-
negatives. After tissue typing and other requi-
site technical protocols, the researchers estab-
lished the B40-positive patients who were
treated with PSK (3 grams daily, two one-
month courses each year) in addition to che-
motherapy had 100-percent survival after 10
years,
47
as shown in Figure 4f. The statistical
significance compared to the no-PSK chemo-
therapy group was clear (p<0.05); B40-nega-
tive patients treated with PSK had approxi-
mately 50-percent survival at 10 years, which
was not statistically significant.
These provoca-
tive findings suggest breast cancer patients
may well benefit from taking PSK in conjunc-
tion with chemotherapy. Patients positive for
HLA B40 antigen may derive great benefit
from taking PSK; those who are negative may
benefit little or not at all.
PSK in Leukemias (ANLL, ALL)
Acute non-lymphocytic leukemia
(ANLL) can be forced into initial remission
using aggressive chemotherapy, but remission
is often short-lived.
48
In a multi-center
Japanese trial on 67 patients with ANLL who
were initially in remission after combination
chemotherapy, patients were randomized to
maintenance chemotherapy or maintenance

Page 16 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
chemotherapy plus PSK 3 grams per day.
Maintenance chemotherapy was terminated at
two years and PSK was continued for the study
duration. Survival was followed to
approximately 4.5 years. The statistical
analysis suggested only a trend toward benefit
from PSK (p=0.1), which may have been due
to the relatively small number of patients
initially enrolled and the even smaller number
surviving at the end. There was a suggestion
from the data plots that for individuals who
remained in remission for 270 days or longer,
PSK might add a further remission of as much
as 418 days. In another study, PSK did not
significantly benefit children in remission from
acute lymphoblastic leukemia.
49
PSK Conclusion
While PSK is not a panacea for can-
cers, it can improve five-year survival in some
indications by as much as double, and perhaps
extend survival to as much as 15 years (see
Figure 4). In some patient subsets, such as
HLA B40-positive breast cancer, or in the pres-
ence of risk factors such as impaired immu-
nity or high ACT or SA, PSK can be espe-
cially life-saving. PSK also helps conserve
immune status in the face of toxic challenge
by conventional treatments.
88
After a quarter-
century of trials indicating PSK can improve
cancer survival, the cumulative human find-
ings amount to a recommendation for its in-
clusion in standard anticancer protocols. With
its risks for adverse effects virtually nonexist-
ent, PSK’s contribution to the benefit-risk pro-
files of these protocols can only be positive.
PSP: Coriolus versicolor
Polysaccharide-P Extract
PSP (“Polysaccharide-P,” poly-
saccharopeptide) is prepared from cultured
mycelium of the COV-1 strain of Coriolus
versicolor.
22,50
PSP may contain as many as
four discrete molecules, all of which are likely
to be true proteoglycans. Chromatographic and
spectral data from infrared nuclear magnetic
resonance and proton resonance are consistent
with PSP being polypeptide (small protein)
moieties with polymeric monosaccharide
chains attached.
The polypeptides in PSP resemble
those of the closely-related proteoglycan PSK,
in that they are enriched with aspartic and
glutamic acids.
51
However, PSP differs from
PSK in its saccharide makeup, lacking fucose
and carrying arabinose and rhamnose. The
polysaccharide chains are true beta-glucans:
gas chromatography-mass spectrometry dis-
closed mainly 1-4, 1-2, and 1-3 glucose link-
ages, together with small amounts of 1-3, 1-4,
and 1-6 galactose, 1-3 and 1-6 mannose, and
1-3 and 1-4 arabinose linkages. A few alpha-
linkages are probably also present. The mo-
lecular weight of PSP is approximately
100,000 daltons,
51
and it is routinely delivered
orally.
Clinical research with PSP has taken a
fast track since it was isolated in 1983 (for a
history, see Yang
52
). With Phase I, II, and III
human trials now completed, PSP has been
proven to be non-toxic,
21,53-55
with marked
immunopotentiation capacity sufficient to im-
prove survival rate and quality of life in can-
cer patients.
21,50
The Phase I trial provided PSP
at doses up to 6 grams per day for one month
to 16 healthy persons and five breast cancer
patients. Appetite increased in a majority of
the subjects, and in this and other preliminary
trials no evidence was found for serious ad-
verse effects.
56,57
The Phase II
58
and Phase III
59
trials established that PSP benefits patients
with stomach, esophageal, and non-small-cell
lung cancers, while substantially protecting
against the unpleasant effects of both the can-
cers per se and the toxic therapies convention-
ally employed to treat them.
60,61
In the Phase II double-blind trial, con-
ducted in 1992 at several hospitals in Shang-
hai, 274 patients with stomach, esophageal, or
lung cancers were dosed with PSP or shark
liver oil (batyl alcohol).
62
Patients received

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 17
Figure 4a-f. Clinically significant extension of survival by PSK, in various cancers
treated also using conventional chemotherapy and/or radiotherapy. Top, left:
stomach, 5-year.
32
Top, right: stomach, advanced, with invasion and metastasis, 15-
year.
31
Middle, left: colon, 5-year.
37
Middle, right: nasopharyngeal, 5-year.
41
Bottom,
left: Breast, stage II, HLA B40-positive, 10-year.
47
Bottom, right: lung (non-small
cell), 5-year.
42
Figure 4e.
100
50
0
0 5 10 15
PSK with chemotherapy
PSK with no chemotherapy
Survival period (years)
Patients alive %
PSK group
Standard treatment group
p=0.044
0 12243648607284
100
90
80
70
60
50
40
30
20
10
0
Follow-up (mo)
Patients alive (%)
Overall survival
100
90
80
70
60
50
40
30
20
10
0
012345
P=0.0430
Survival period (years)
B
PSK
No PSK
Patients alive %
100
90
80
70
60
50
40
30
20
10
0
Survival period (months)
PSK
No PSK
Patients alive %
0 10203040506070 90 80
100
50
0
012345
Survival period (years)
Patients alive %
58%
27%
22%
7%
Figure 4f.
Figure 4c.
Figure 4d.
Figure 4a.
Figure 4b.
100
80
60
40
20
0
5
10
Survival period (years)
Patients alive %
HLA B40+ with PSK
HLA B40- with PSK

Page 18 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
conventional anticancer therapies (radio-
therapy and/or chemotherapy), following sur-
gery where appropriate. The PSP dose was 3.1
grams/day, the batyl alcohol 450 mg/day, taken
by mouth before meals for two months. Ef-
fectiveness was judged by marked improve-
ment of clinical symptoms together with; (a)
significant improvement in blood profiles
(white cell count, other) and/or immune indi-
ces; and/or (b) significant improvement in
Karnovsky performance status or body weight.
If none of these criteria for effectiveness was
met in a patient at the end of the trial period
(six months), the treatment was judged inef-
fective.
Once the code was broken at the end
of the trial and the data analyzed, PSP was
found effective for 82 percent of the patients
versus 45 percent for batyl alcohol (p<0.001).
PSP improved clinical symptoms overall. PSP
alleviated symptoms commonly associated
with cancer, including fatigue, anorexia, nau-
sea, thirst, cold sweat, and pain. PSP also al-
leviated the severity of systemic toxic dete-
rioration associated with conventional thera-
pies, stabilized or increased body weight, and
significantly improved overall immune status.
The extent of benefit to patients with specific
cancer types is summarized in Table 3.
The success of the Phase II trial justi-
fied progression to a well controlled 17-month,
multi-center Phase III trial, which was carried
out at hospitals in Shanghai, Beijing, and other
areas in China, with a total 189 patients. The
double-blind study used the same doses and
test materials as the previous study, and ex-
amined PSP against the same three cancers co-
treated with conventional therapies.
59
PSP was
effective in 87 percent of patients, versus 42
percent for the shark alcohol (p<0.01), using
the same criteria for effectiveness as the Phase
II trials.
59
Fatigue, loss of appetite, anorexia,
vomiting, dryness of mouth or throat, sweat-
ing, and pain all were significantly decreased
(p<0.05). PSP lessened fatigue in the greatest
number of patients (81 percent) and pain in
the least number (26 percent). PSP also im-
proved most of the other parameters measured
in this Phase III trial.
59
Karnovsky performance
status significantly improved in 95 percent of
the patients (compared to 22% of the controls,
p<0.05). White cell count and hemoglobin
were significantly improved, as well as
interleukin-2, which helps activate killer cells.
CD4/T-helper counts were conserved more
than in controls, as was the CD4/CD8 ratio.
Body weight was maintained and PSP pro-
duced no adverse effects.
In the Phase III trial, as well as a num-
ber of reports from individual treatment cen-
ters, PSP again demonstrated significant ben-
efit against three cancers – stomach, esopha-
gus, and lung.
21,50,63
PSP also ameliorated ad-
verse effects to the bone marrow, liver, skin,
and cardiovascular and digestive systems seen
in batyl alcohol controls.
50
Sun et al quanti-
fied the adverse side-effects attributable to the
chemotherapy and radiotherapy regimens, and
found markedly lower incidence in the PSP-
treated group.
61
Although the Phase II and III trial de-
signs did not include assessment of long-term
survival benefit, in an open-label, randomized
trial on esophageal cancer, PSP did signifi-
cantly improve one-year and three-year sur-
vival.
64
In his cogent 1999 review of PSP, Liu
noted PSP also has favorable action in patients
receiving bone marrow transfusion (BMT)
treatment.
65
Taken together, the findings from
the Phase II and Phase III trials establish that
PSP benefits cancers of the stomach,
62,66-68
esophagus,
62,63,69-71
and lung,
62,72-76
and PSP has
been recognized for these applications by
China’s Ministry of Public Health.
As shown in Table 3, the percentage
of patients who experienced benefit from PSP
in the Phase II and Phase III trials ranged from
90-97 percent for stomach, 82-87 percent for
esophageal, and 70-86 percent for lung
cancers, all statistically significant when

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 19
Cancer Type Authors Subjects Outcome
Stomach Liu et al, 1993
62
78 PSP effective 97% pts. vs. 77%
DOUBLE-BLIND PSP vs shark oil controls (p<0.01). Marked
Phase II trial symptomatic improvement
Stomach Zhang et al, 1993
89
18 PSP increased NK cells
DOUBLE-BLIND PSP vs shark oil (p<0.05)
Subgroup Phase II
Stomach Shi, 1993
90
30 PSP increased NK cells
DOUBLE-BLIND PSP vs shark oil (p<0.01)
Subgroup Phase II
Stomach Liu et al, 1999
59
60 PSP effective 90% pts. vs 40%
DOUBLE-BLIND PSP vs shark oil controls (p<0.01)
Phase III trial
Stomach Wu et al, 1999
91
82 PSP increased NK, IL-2,
OPEN PSP vs shark oil CD4/CD8 ratio (p<0.01)
Esophagus Liu and Zhou, 1993
62
112 PSP effect. 82% pts. vs. 32%
DOUBLE-BLIND PSP vs shark oil (p<0.001). Marked
Phase II trial symptomatic improvement
Esophagus Yao, 1999
64
100 PSP extended 1-yr, 3-yr
OPEN Surg + RT +/-PSP survival (p≤0.05)
Esophagus Liu et al, 1999
59
61 PSP effective 87% pts. vs. 43%
DOUBLE-BLIND PSP vs shark oil controls (p<0.01)
Phase III trial
Lung Liu and Zhou, 1993
62
84 PSP effective 70% pts. (>2x
DOUBLE-BLIND PSP vs shark oil controls) (p<0.01). Marked
Phase II trial symptomatic improvement
Lung Liu et al, 1999
59
68 PSP effective 86% pts. vs. 42%
DOUBLE-BLIND PSP vs shark oil controls (p<0.01)
Phase III trial
Gynecological Sun and Zhu, 1999
60
40 PSP improved quality of life
(Ovarian, Chemotherapy +/-PSP (p<0.05)
Endometrial)
*Where indicated, conducted within two larger, compounded Phase II and Phase III trials. Herein
listed separately for clarity. Statistical data listed as derived by the trial investigators.
Table 3. PSP Controlled Trials Against Various Cancers.

Page 20 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
compared against figures for controls. Clearly,
PSP can benefit the majority of patients
afflicted with such cancers, and has the
potential to be therapeutic against other
cancers as well.
73,77
Mushroom Immunoceuticals:
Mechanisms of Action
The orally-bioactive glucans and
proteoglycans isolated from mushrooms are
currently the most promising class of
immunoceuticals. Without doubt, they are ca-
pable of simultaneously augmenting all the key
pathways of host immunity. After decades of
experimentation with lentinan, PSK,
schizophyllan, and PSP, as many potential
mechanisms have been identified as the many
pathways known to exist in the immune sys-
tem. Perhaps the single most logical and likely
site of action is in dendritic or Langerhans cells
(LC).
Dendritic cells, of which Langerhans
cells are a skin-residing subset, are capable of
sensing foreign or domestically-threatening
material and mobilizing an appropriate, timely
immune response. PSK injected directly into
human stomach tumors prior to surgery was
taken up specifically by dendritic cells located
in and around the tumors.
78
Tsujitani, Maehara,
and their coworkers successfully correlated ex-
tended survival of stomach cancer patients
with the degree of infiltration of the tumors
by LC.
34,79
Due to their widespread localization
throughout tissues, dendritic cells are the first
cellular line of defense of the immune system.
They are likely to be the first host cells to con-
tact incoming glucan material. As glucans en-
ter the oral cavity, they can be sampled by the
LC present in the oral mucosa, and then by
dendritic cells in the stomach and intestines.
After glucan materials are absorbed and cir-
culate to the liver, the dendritic-like Kupffer
cells can sample them. Glucan material reach-
ing lymph nodes can be taken up by dendritic
cells residing in the nodes. Carbon-14 radio-
labeling of PSK was utilized to prove its large
proteoglycan molecules are absorbed and
reach the bloodstream intact.
23
Similar to PSK stimulating dendritic
cells, PSP is known to stimulate macrophage
or other immune phagocytic activity in vivo.
When mice were given charcoal intravenously,
then fed PSP, both the phagocytic activity of
cells in the blood and the clearance of the char-
coal from the circulation were significantly
accelerated.
80
These “upstream” activation effects of
PSK and PSP on tissue and blood-borne ph-
agocytic cells likely account for their “down-
stream” effects, which effectively result in
heightened anticancer immunity. It is tempt-
ing to imagine after being picked up by a den-
dritic cell or other antigen-sorting cell, PSK
and PSP may function as antigenic stimuli.
Perhaps their presence above a certain thresh-
old inside a phagocytic immune cell, while
innocuous to the cell’s survival, in some way
activates or primes that cell. Perhaps mush-
room glucans and proteoglycans act more
crudely, “prodding” the cell to greater antigen-
presenting activity.
In killer or pre-killer T-cells, it is pos-
sible the close proximity of these
immunoceutical substances to the outer cell
membrane could result in activation or height-
ening of activity. Elevated cytotoxic, killer cell
activity has been linked in vivo to a more posi-
tive post-operative clinical course in cancer
patients.
81,82
PSK activates killer cells in vivo.
The instillation of PSK into a human gastric
tumor mass prior to resective surgery caused
T-cells around the site to become tumor-infil-
trating and develop significantly enhanced
cytotoxic “killer” activity directed at the tu-
mor. Similar findings were obtained with a 14-
day course of PSK in bladder cancer patients.
82
PSK also activates human NK cells in culture
at concentrations reached in the blood by nor-
mal oral dosing of 3 grams per day.
81,82

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 21
PSP also activates killer cells in situ in
the living cancer patient. In the Phase II and
III double-blind trials, PSP significantly raised
NK cytotoxic activity, significantly raised IL-
2 levels, and significantly improved the CD4
helper/CD8 suppressor T-cell ratio. Altogether,
these are the primary components of antican-
cer immunity.
Adoptive immunotherapy protocols
81
aim to remove potential killer cells from the
patient, activate them with the cytokine IL-2
(interleukin-2), then return them to the body
to attack cancerous tissue. But the IL-2 doses
required to trigger activation of CD4 and NK
cells can have major adverse side-effects. Con-
comitant dosing of such cells with PSP can
cut the required amount of IL-2 by at least half.
PSP stimulates lymphokine-activated killer
(LAK) cell proliferation by itself at relatively
low concentrations and in the absence of IL-
2.
83
In mice with suppression of IL-2 produc-
tion from cyclophosphamide toxicity, PSP
supplementation restored IL-2 production to
normal.
51
Another potential avenue of mushroom
immunoceutical action is through elevation of
immune system cytokines in vivo. PSK, PSP,
lentinan, and other mushroom
immunoceuticals can provoke secretion of
cytokines, including IL-1, IL-2, IL-6, IL-8,
TNF (tumor necrosis factor) and various
interferons from cultured immune cells by as
much as 5-120 times baseline levels.
1,2
How-
ever, experiments in which antibodies were
used to block the actions of individual
cytokines clearly demonstrated cytokines were
not necessary for PSK to activate human natu-
ral killer cells.
81
This finding points to pos-
sible cell-to-cell interactions, rather than phar-
macologic cytokine activity, as the main fo-
cus of mushroom immunoceuticals. The
former class of effect would also be more con-
sistent with their pro-homeostatic effects,
rather than the adverse effects associated with
the use of cytokines in human trials.
A critical assessment of the
mechanistic findings from human studies of
various mushroom immunoceuticals led to the
Colony-
stimulating
factors
Thymus,
bone marrow
activation
Complement C3
Liver
Increase of
Immuno-
competent
cell number
Cancer cell
killing, inhibition
of metastasis
Antibodies
Tum or
antigen
Proteoglycan
β Glucan
Mature
T-cells
Monocytes
Macrophages
Activated
Macrophages
CD4
T Lymphocytes
(helper)
Cytotoxic
T Lymphocytes
(precursor)
Cytotoxic
T Lymphocytes
B Lymphocytes
Natural killer
cells (NK)
Tissue
Macrophages
(antigen-
presenting)
Figure 5. Likely pathways for immune enhancement by mushroom proteoglycans.
Modified, from Chihara et al.
8

Page 22 Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000
composite schematic presented in Figure 5.
Many details of mushroom immunoceutical
actions are unclear, but their clinical versatility
should provide impetus for more precise
definition of their modes of action.
Mushroom Immunoceuticals:
Valuable Anticancer Tools
A trend toward integration of
immunopotentiating agents with the extant
cancer regimens of surgery, chemotherapy, and
radiation therapy is now considerably ad-
vanced in Japan and China – countries where
mushroom preparations have been an antican-
cer resource for centuries. In the West, a more
proactive approach to cancer management is
long overdue, with the glaring failures of con-
ventional modalities to cure common cancers
and the availability of good clinical evidence
supporting mushroom immunoceuticals. Mis-
placed dogma should soon give way to a new
round of clinical and basic research aimed at
melding this immunotherapy approach into
qualitative improvement of cancer survival
rates.
The most frequent cause of shortened
survival of the patient with cancer is metasta-
sis, occurring with or without invasion of the
surrounding tissues by the formed tumors.
Surgery often successfully reduces the tumor
mass, and chemotherapy or radiation therapy
sometimes will further reduce detectable tu-
mors and minimize invasiveness and metasta-
sis. However, these toxic therapies invariably
damage host immunity, and small invasive
masses or malignant cell clumps (as little as
100,000 cells or less) predictably survive the
best efforts to eradicate them. With their ca-
pacity to mobilize the immune system against
formed tumors as well as metastases, while
lessening the adverse side-effects of conven-
tional therapies, mushroom immunoceuticals
should offer clinically-attractive options to the
thinking oncologist.
Mushroom immunoceuticals compare
favorably with classic biological response
modifiers, such as BCG, OK-432, LAK cells,
or purified cytokines such as interferons, tu-
mor necrosis factor, or interleukin-2. All these
are capable of causing fever, chills, rash,
edema, arthralgia, hypotension, congestive
heart failure, or CNS toxicities.
65
Crude yeast
cell wall material, currently being represented
as beta-glucan concentrates, reportedly can
cause fevers and other problems. The standard-
ized mushroom glucans and polysaccharide-
peptide preparations cause no fever, allergy,
or other type of intolerance.
2
With the emergence of putative mark-
ers by which their likelihood of efficacy can
be monitored – dendritic cell tumor infiltra-
tion, killer cell cytotoxic potential in vitro,
abnormally-low skin DTH, elevated levels of
ACT or SA – these safe and effective mush-
room immunopotentiators are prime choices
for cancer management. In fact, progressive
physicians have been using them for years.
Certainly the risk-benefit and cost-benefit pro-
files of mushroom preparations are superior
to anticancer pharmaceuticals. Besides being
safe to take for periods of years, they improve
energy levels in the cancer patient, speed re-
generation of damaged bone marrow, support
the liver,
84
reduce side-effects of toxic antican-
cer therapies, and generally raise well-being.
PSP also offers analgesic action, which can
be beneficial to the cancer patient. Doses up
to 15 grams daily have been tolerated long-
term without noticeable adverse effects.
59
Although it has been less thoroughly
researched overall than PSK and its long-term
benefits to survival are not yet as firmly estab-
lished, PSP is fast gaining respect as an anti-
cancer therapeutic. Strictly controlled, double-
blind trials demonstrated PSP improves qual-
ity of life in more than 70 percent of patients
with cancer. PSP also lessens the adverse ef-
fects of other therapies, while potentiating their
curative effects.
50,85
For practitioners hesitant
to put full faith in PSP due to its relative lack

Mushroom Glucans & Proteoglycans
Alternative Medicine Review
◆ Volume 5, Number 1 ◆ 2000 Page 23
of survival data, the use of a combination of
PSP with PSK might be worthy of consider-
ation.
The enhanced survival rates achieved
by PSK for several cancers are certainly clini-
cally meaningful. Used singly or in combina-
tion, PSK and PSP have the potential to ex-
tend survival. It may prove instructive, for pro-
ponents and skeptics alike, to conduct an inte-
grative cancer trial in which mushroom
immunoceuticals play a central role, along
with digestive enzymes, thymic extract, vita-
min C, coenzyme Q10, omega-3 fatty acids,
and other positive-acting immunoceuticals.
Glucan and proteoglycan mushroom
immunoceuticals offer hope for cancer pa-
tients. These substances are pro-homeostatic,
uniquely effective immune boosters, which
pose no threat of autoimmune backlash. As
dietary supplements, they are safe, clinically
proven, and exhibit near-perfect benefit-risk
profiles. Mushroom immunoceuticals are a
potential boon to individuals afflicted with
cancer, living with impaired immunity, or
merely descending into ill health with the pass-
ing of time.
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